Delayed puberty and early-onset type 2 diabetes risk: a nationwide cohort study of male adolescents in Israel.
Delayed puberty has been associated with adverse metabolic outcomes, yet longitudinal evidence on its relation to type 2 diabetes risk is scarce. We aimed to investigate the association between delayed puberty during adolescence and early-adult-onset type 2 diabetes in male adolescents.
This nationwide, population-based, retrospective cohort study included Israeli male adolescents aged 16-19 years who were examined before military recruitment during 1992-2015 and followed up until Dec 31, 2019. Exclusion criteria were diabetes at the baseline medical assessment, hypogonadotropic hypogonadism, missing height or weight data, and death before the establishment of the Israeli National Diabetes Registry (INDR) in 2012. Delayed puberty was diagnosed by board-certified paediatric endocrinologists, based on physical examinations and laboratory evaluations. By linking data to the INDR, diabetes was identified by: glycated haemoglobin concentrations of more than 6·5%, serum glucose concentrations of more than 200 mg/dL in two tests at least 1 month apart, or repeated purchases of glucose-lowering medications. Type 2 diabetes was classified according to medication records, which underwent quality assessment to ensure accuracy. Cox proportional hazards models were applied.
The study included 964 108 Israeli male adolescents (mean age at evaluation 17·3 years [SD 0·5]). Delayed puberty was diagnosed in 4307 males, whereas 959 801 did not have delayed puberty. During a cumulative follow-up of 15 242 068 person-years, type 2 diabetes was diagnosed in 111 (2·6%) individuals with delayed puberty (mean age at diagnosis 35·5 years [SD 5·2]) and 6259 (0·7%) individuals without delayed puberty (36·8 years [4·7]). The respective incidence rates of type 2 diabetes were 140·3 cases per 105 person-years (95% CI 114·2-166·4) and 41·3 cases per 105 person-years (40·3-42·3; p<0·0001); absolute difference 99·0 (72·9-125·1). After adjustment for age, year of study entry, education, cognitive performance, residential socioeconomic status, and country of birth, delayed puberty was associated with an increased risk of type 2 diabetes (hazard ratio [HR] 2·47 [95% CI 2·04-2·99], p<0·0001). Additional adjustment for baseline BMI attenuated but did not eliminate the association (HR 1·37 [1·13-1·66]; p=0·0015). The findings persisted across extensive sensitivity analyses.
Male adolescents with delayed puberty are at increased risk of developing type 2 diabetes in early adulthood, independent of BMI. Our findings suggest that delayed puberty is not a benign developmental variant, but might serve as an early marker of increased risk for later abnormal glucose metabolism.
Sheba Medical Center.
This nationwide, population-based, retrospective cohort study included Israeli male adolescents aged 16-19 years who were examined before military recruitment during 1992-2015 and followed up until Dec 31, 2019. Exclusion criteria were diabetes at the baseline medical assessment, hypogonadotropic hypogonadism, missing height or weight data, and death before the establishment of the Israeli National Diabetes Registry (INDR) in 2012. Delayed puberty was diagnosed by board-certified paediatric endocrinologists, based on physical examinations and laboratory evaluations. By linking data to the INDR, diabetes was identified by: glycated haemoglobin concentrations of more than 6·5%, serum glucose concentrations of more than 200 mg/dL in two tests at least 1 month apart, or repeated purchases of glucose-lowering medications. Type 2 diabetes was classified according to medication records, which underwent quality assessment to ensure accuracy. Cox proportional hazards models were applied.
The study included 964 108 Israeli male adolescents (mean age at evaluation 17·3 years [SD 0·5]). Delayed puberty was diagnosed in 4307 males, whereas 959 801 did not have delayed puberty. During a cumulative follow-up of 15 242 068 person-years, type 2 diabetes was diagnosed in 111 (2·6%) individuals with delayed puberty (mean age at diagnosis 35·5 years [SD 5·2]) and 6259 (0·7%) individuals without delayed puberty (36·8 years [4·7]). The respective incidence rates of type 2 diabetes were 140·3 cases per 105 person-years (95% CI 114·2-166·4) and 41·3 cases per 105 person-years (40·3-42·3; p<0·0001); absolute difference 99·0 (72·9-125·1). After adjustment for age, year of study entry, education, cognitive performance, residential socioeconomic status, and country of birth, delayed puberty was associated with an increased risk of type 2 diabetes (hazard ratio [HR] 2·47 [95% CI 2·04-2·99], p<0·0001). Additional adjustment for baseline BMI attenuated but did not eliminate the association (HR 1·37 [1·13-1·66]; p=0·0015). The findings persisted across extensive sensitivity analyses.
Male adolescents with delayed puberty are at increased risk of developing type 2 diabetes in early adulthood, independent of BMI. Our findings suggest that delayed puberty is not a benign developmental variant, but might serve as an early marker of increased risk for later abnormal glucose metabolism.
Sheba Medical Center.
Authors
Pinhas-Hamiel Pinhas-Hamiel, Simchoni Simchoni, Derazne Derazne, Bendor Bendor, Tsur Tsur, Vinograd Vinograd, Lutski Lutski, Zucker Zucker, Singhal Singhal, Gerstein Gerstein, Afek Afek, Tirosh Tirosh, Twig Twig
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